Premium
Cancer Cell‐induced Suppression of Cytotoxic Alu RNA Biosynthesis in the Co‐cultured Macrophages
Author(s) -
Singhal Ashutosh,
Mishra Smita,
Chaudhuri Gautum
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.578.10
Subject(s) - rna , cytotoxic t cell , cancer cell , biology , microbiology and biotechnology , chemistry , cancer , biochemistry , gene , genetics , in vitro
Macrophages are among the immune cells that are recruited at the site of solid tumor to phagocytose tissue debris and to destroy the tumor cells through phagocytosis‐induced inflammatory immune response. Thus, unless manipulated by the cancer cells, the inflammatory response induced in the macrophages should kill the macrophages bringing collateral damage to the tumor cells. One of the emerging mechanisms of induction of inflammatory response in the macrophages is the increase in the level of cytotoxic scAlu RNA in these cells. Through the enhancement of reactive oxygen species levels, scAlu RNA activates NLRP3 inflammasome in these cells to cause cell death via the caspase pathway. We found that macrophages co‐cultured with aggressive, but not with the non‐aggressive, breast cancer cells are manipulated by the suppression of their scAlu RNA biosynthesis. Alu RNA, the precursor of scAlu RNA, is transcribed by RNA polymerase III and requires TFIIIC110 for their expression. We found that the metalloproteinase MMP1, secreted by the aggressive breast cancer cells, proteolytically activates the G‐protein‐coupled receptor PAR1 on the surface of the macrophages. Activation of PAR1 elevated the cytosolic Ca 2+ levels through the Galpha‐q/PIPLC/PIP3 pathway thereby activating the Ca 2+ ‐dependent protease mu‐calpain. The TFIIIC110 protein, which has a mu‐calpain target PES sequence, was degraded by mu‐calpain resulting in the suppression of Alu RNA biosynthesis. Suppression of Alu RNA levels consequently decreased the levels of its processed derivative, the scAlu RNA, preventing the induction of inflammatory response in the macrophages. This research is supported in part by NIH/NCI grant 1R21CA181920‐01 to GC.